Department of Obstetrics and Gynecology, University of Düsseldorf Medical Center, Moorenstrasse 5, 40225 Düsseldorf, Germany.
J Cancer Res Clin Oncol. 2012 Apr;138(4):603-10. doi: 10.1007/s00432-011-1135-5. Epub 2012 Jan 1.
Targeted oncolytic adenoviruses capable of replication selectively in cancer cells are an appealing approach for the treatment of various cancer types refractory to conventional therapies. The aim of this study was to evaluate the effect of Ad5/3MDR1E1, a multidrug resistance gene 1 (MDR1)-targeted fiber-modified replication-competent adenovirus for the therapy of platinum-pretreated ovarian cancer in combination with cytostatic agents.
MDR1-specific tumor cell killing of Ad5/3MDR1E1 was systematically evaluated in chemotherapy naïve and pretreated ovarian cancer cells in vitro. Combinations of Ad5/3MDR1E1 and cytostatic agents were studied in vivo and in vitro. An in vivo hepatotoxicity model was used to evaluate liver toxicity.
We demonstrate efficient oncolysis of Ad5/3MDR1E1 in chemotherapy-resistant ovarian cancer cells as well as therapeutic efficacy in an orthotopic mouse model. Further, combining Ad5/3MDR1E1 with paclitaxel resulted in greater therapeutic benefit than either agent alone.
These preclinical data suggest that a fiber-modified adenovirus vector under the control of the MDR1 promoter represents a promising treatment strategy for platinum-pretreated ovarian cancer as a single agent or in combination with conventional anticancer drugs.
能够在癌细胞中选择性复制的靶向溶瘤腺病毒是治疗各种对传统疗法耐药的癌症类型的一种有吸引力的方法。本研究旨在评估 Ad5/3MDR1E1（一种多药耐药基因 1（MDR1）靶向纤维修饰的复制型腺病毒）对联合细胞毒药物治疗铂预处理卵巢癌的疗效。
在体外，系统评估了 Ad5/3MDR1E1 对化疗初治和预处理卵巢癌细胞的 MDR1 特异性肿瘤细胞杀伤作用。研究了 Ad5/3MDR1E1 与细胞毒药物的体内和体外组合。使用体内肝毒性模型来评估肝脏毒性。
我们证明了 Ad5/3MDR1E1 在化疗耐药卵巢癌细胞中的有效溶瘤作用，以及在原位小鼠模型中的治疗效果。此外，与单独使用任一药物相比，将 Ad5/3MDR1E1 与紫杉醇联合使用可带来更大的治疗益处。
这些临床前数据表明，受 MDR1 启动子控制的纤维修饰腺病毒载体作为单一药物或与传统抗癌药物联合使用，代表了治疗铂预处理卵巢癌的一种有前途的治疗策略。
